A negative feedback loop exists between the immune and central nervous systems, in which immune/pro-inflammatory mediators signal the hypothalamic-pituitary-adrenal axis to induce glucocorticoid mediated restraint of the immune response. We have established the physiologic significance of this feedback loop in our studies in Lewis (LEW/N) rats, in which we have shown that susceptibility to inflammatory arthritis is related to a defect in the central component of this negative feedback loop, resulting in deficient CRH responses to challenge with a variety of inflammatory and stress mediators. We now extend these initial studies to show that the LEW/N CRH hyporesponsiveness, relative to other strains, is profound, and extends across a variety of neurotransmitters and behavioral stressors; it occurs as early in ontogeny as postnatal Day 14; it is associated with a variety of defined behavioral patterns, consistent with the differential HPA axis responsiveness. Although several neurotransmitter systems to not differ in these strains (norepinephrine, 5HT2, acetylcholine), we have identified three neurotransmitter systems important in regulation of CRH which do differ in these strains: the benzodiazepine/GABA receptor complex, 5-HT1A system, and glucocorticoid Type 1 and type 2 receptor systems differ in receptor number and/or ligand metabolism in these strains. The differences are organ and/or CNS site specific, and may be secondary to or play a causal role in the CRH hyporesponsiveness, and could contribute to or amplify some of the behavioral and/or inflammatory disease phenotypes in these strains. While the LEW/N rat represents an example of a genetically based HPA axis hyporesponsivess associated with susceptibility to inflammatory and behavioral disease, the L-tryptophan eosinophilia myalgia syndrome may represent a toxic syndrome in which a neurotransmitter-related molecule may both induce inflammatory disease by a direct action on the immune system, and amplify inflammation indirectly through suppression of the HPA aix. We first described this syndrome and studied its biochemistry in humans in relation to L-5-hydroxytryptophan in 1980 and in relation to L-tryptophan in 1990. We have established the first animal model for this syndrome in LEW/N rats, and have determined that one of the main impurities (EBT) causes fascial thickening in these rats, the hallmark of this syndrome. We have established a molecular mechanism through which the breakdown product of this impurity may induce fibrosis and cause CNS pathology through a specific receptor mediated mechanism.